Abstract
Objective
The aim of this study was to investigate the acute effects of methylene blue (MB), an inhibitor of thel-arginine nitric oxide pathway, in patients with septic shock.
Design
A prospective, open, single-dose study.
Setting
The medical ICU of a university hospital.
Patients
Six patients with severe septic shock.
Interventions
Complete hemodynamic values were recorded before and 20 min after the infusion of intravenous MB (3 mg kg−1). Arterial pressure was then monitored during the next 24 h or until death.
Measurements and results
Methylene blue increased the mean arterial pressure from 69.7±4.5 to 83.7±5.1 mmHg (p=0.028) and the mean pulmonary artery pressure, from 34.3±7.2 to 38.7±8.0 mmHg (p=0.023). Systemic vascular resistance index was increased from 703.1±120.6 to 903.7±152.2 dyne.s.cm−5.m−2 (p=0.028) and pulmonary vascular resistance index, from 254.6±96.9 to 342.2±118.9 dyne.s.cm−5.m−2 (p=0.027). The PaO2/FIO2 decreased from 229.2±54.4 to 162.2±44.1 mmHg (p=0.028), without significant modification of intrapulmonary shunting. Heart rate, cardiac index, right atrial pressure, DO2, VO2, oxygen extraction and arterial lactate were essentially unchanged. Sequential measurements of arterial pressure demonstrated a return to baseline level in 2–3 h. All but one patients died, three in shock and two in multiple organ failure.
Conclusions
MB induces systemic and pulmonary vasoconstriction in patients with septic shock, without significant decrease in cardiac index. The worsening of arterial oxygenation following MB injection may limit its use in patients with the adult respiratory distress syndrome. Larger studies are required to determine whether MB improves the outcome of patients with septic shock.
References
Parker MM, Shelhamer JH, Natanson C, Alling D, Parillo JE (1987) Serial hemodynamic patterns in survivors and non-survivors of septic shock in humans. Crit Care Med 15: 923–929
Lowenstein CJ, Dinerman JL, Snyder SH (1994) Nitric oxide: a physiologic messenger. Ann Intern Med 120: 227–237
Moncada S, Higgs A (1993) Thel-arginine-nitric oxide pathway. N Engl J Med 329: 2002–2012
Clutton-Brock J (1967) Two cases of poisoning by contamination of nitrous oxide with higher oxides of nitrogen during anaesthesia. J Anaesth 39: 388–392
Hall HA, Kulig KW, Rumack BH (1986) Drug and chemical-induced methaemo-globinaemia: clinical features and management. Med Toxicol 1: 253–260
Mayer B, Brunner F, Schmidt K (1993) Inhibition of nitric oxide synthesis by methylene blue. Biochem Pharmacol 45: 367–374
Henry Y, Lepoivre M, Drapier JC, Ducrocq C, Boucher JL, Guissani A (1993) EPR characterization of molecular targets for NO in mammalian cells and organelles. FASEB J 7: 1124–1134
Julou-Schaeffer G, Gray GA, Fleming I, Schott C, Parratt JR, Stoclet JC (1990) Loss of vascular responsiveness induced by endotoxin involvesl-arginine pathway. Am J Physiol 259: H1038-H1043
Fleming I, Gray GA, Julou-Schaeffer G, Parratt JR, Stoclet JC (1990) Incubation with endotoxin activates thel-arginine pathway in vascular tissues. Biochem Biophys Res Commun 171: 562–568
Paya D, Gray GA, Stoclet JC (1993) Effects of methylene blue on blood pressure and reactivity to norepinephrine in endotoxemic rats. J Cardiovasc Pharmacol 21: 926–930
Preiser JC, Zhang H, Vincent JL (1994) Administration of methylene blue in septic shock: is it beneficial? In: Vincent JL (ed) Yearbook of intensive care and emergency medicine. Springer, Berlin Heidelberg New York, pp 90–100
Schneider F, Lutun P, Hasselmann M, Stoclet JC, Tempé JD (1992) Methylene blue increases systemic vascular resistance in human septic shock. Intensive Care Med 18: 309–311
Le Gall JR, Loirat P, Alperovitch A, et al (1984) A simplified acute physiology score for ICU patients. Crit Care Med 12: 975–977
Bone RC, Balk RA, Cerra FB, et al (1992) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 101: 1644–1662
Knaus WA, Wagner DP, Draper EA, Zimmerman JE (1985) Prognosis in acute organ system failure. Ann Surg 202: 685–692
Murray JF, Matthay MA, Luce JM, Flick MR (1988) An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 138: 720–723
Tran DD, Groeneveld ABJ, Van der Meulen J, Nauta JJP, Strack Van Schijndel RJM, Thijs LG (1990) Age, chronic disease, sepsis, organ system failure, and mortality in a medical intensive care unit. Crit Care Med 18: 474–479
Klabunde RE, Ritger RC (1991) NG-monomethyl-l-arginine (NMA) restores arterial blood pressure but reduces cardiac output in a canine model of endotoxic shock. Biochem Biophys Res Commun 178: 1135–1140
Cobb JP, Natanson C, Hoffman WD et al (1992) Nω-amino-l-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin. J Exp Med 176: 1175–1182
Lorente JA, Landin L, Renes E, et al (1993) Role of nitric oxide in the hemodynamic changes of sepsis. Crit Care Med 21: 759–767
Statman R, Cheng W, Cunningham JN, et al (1994) Nitric oxide inhibition in the treatment of the sepsis syndrome is detrimental to tissue oxygenation. J Surg Res 57: 93–98
Schilling J, Cakmakci M, Battig U, Geroulanos S (1993) A new approach in the treatment of hypotension in human septic shock by NG-monomethyl-l-arginine, an inhibitor of the nitric oxide synthetase. Intensive Care Med 19: 227–231
Lorente JA, Landin L, De Pablo R, Renes E, Liste D (1993)l-Arginine pathway in the sepsis syndrome. Crit Care Med 21: 1287–1295
Petros A, Lamb G, Leone A, Moncada S, Bennett D, Vallance P (1994) Effects of a nitric oxide synthase inhibitor in humans with septic shock. Cardiovasc Res 28: 34–39
Wright CE, Rees DD, Moncada S (1992) Protective and pathological roles of nitric oxide in endotoxin shock. Cardiovasc Res 26: 48–57
Hutcheson IR, Whittle BJR, Boughton-Smith NK (1990) Role of nitric oxide in maintaining vascular integrity in endotoxin-induced acute intestinal damage in the rat. Br J Pharmacol 101: 815–820
Harbrecht BG, Billiar TR, Stadler J, et al (1992) Nitric oxide synthesis serves to reduce hepatic damage during acute murine endotoxemia. Crit Care Med 20: 1568–1574
Shultz PJ, Raij L (1992) Endogenously synthesized nitric oxide prevents endotoxin-induced glomerular thrombosis. J Clin Invest 90: 1718–1725
Robinson DN, McFadzean WA (1990) Pulse oxymetry and methylene blue. Anesthesia 45: 884–885
Rossaint R, Falke KJ, Lopez F, Slama K, Pison U, Zapol WM (1993) Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 328: 399–405
Högman M, Frostell CG, Hedenström H, Hedenstierna H (1993) Inhalation of nitric oxide modulates adult human bronchial tone. Am Rev Respir Dis 148: 1474–1478
Midgley S, Grant IS, Haynes WG, Webb DJ (1991) Nitric oxide in liver failure. Lancet 338: 1590
Author information
Authors and Affiliations
Additional information
The study was supported by the Délégation à la Recherche Clinique, Assistance Publique-Hôpitaux de Paris
Rights and permissions
About this article
Cite this article
Gachot, B., Bédos, J.P., Veber, B. et al. Short-term effects of methylene blue on hemodynamics and gas exchange in humans with septic shock. Intensive Care Med 21, 1027–1031 (1995). https://doi.org/10.1007/BF01700666
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01700666